BCR-ABL1 mediates up-regulation of Fyn in chronic myelogenous leukemia

Blood
Kechen BanJoya Chandra

Abstract

Chronic myelogenous leukemia (CML) invariably progresses to blast crisis, which represents the most proliferative phase of the disease. The BCR-ABL1 oncogene stimulates growth and survival pathways by phosphorylating numerous substrates, including various Src family members. Here we describe up-regulation, in contrast to activation, of the ubiquitously expressed Src kinase, Fyn, by BCR-ABL1. In a tissue microarray, Fyn expression was significantly increased in CML blast crisis compared with chronic phase. Cells overexpressing BCR-ABL1 in vitro and in vivo display an up-regulation of Fyn protein and mRNA. Knockdown of Fyn with shRNA slows leukemia cell growth, inhibits clonogenicity, and leads to increased sensitivity to imatinib, indicating that Fyn mediates CML cell proliferation. In severe combined immunodeficient (SCID) mice injected with Fyn shRNA-expressing cells, myeloid-derived cell numbers dropped by 50% and death from leukemia was delayed. Taken together, these results encourage the development of therapies targeting Fyn expression.

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Citations

Dec 23, 2011·International Journal of Hematology·Noriko DokiToshio Kitamura
Jan 10, 2009·The Journal of Biological Chemistry·Yin GaoJoya Chandra
Aug 21, 2012·Antioxidants & Redox Signaling·Mary E IrwinJoya Chandra
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Oct 2, 2008·Blood·Alfonso Quintás-Cardama, Jorge Cortes
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Jun 2, 2012·Blood·Rüdiger Hehlmann
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Jan 14, 2021·Cells·Valentina R MinciacchiDaniela S Krause
Apr 23, 2013·Journal of Cell Science·Lihi Ninio-ManyRuth Shalgi

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